DESCRIPTION (applicant's abstract): Methamphetamine (METH) abuse has increased across the U.S. at an alarming rate since the late 1980's. Studies on human brain and preclinical studies have revealed that the single or repeated administration of METH results in a long-lasting depletion of brain dopamine (DA) content and other markers associated with DA neurotransmission in the extrapyramidal motor system. Despite these findings, the mechanisms that mediate toxicity to DA neurons following METH remain unknown. Recently, glutamate has been implicated as an important mediator of damage to brain DA systems produced by METH, but the mechanisms underlying the changes in glutamatergic activity that culminate in "excitotoxicity" and damage the nigrostriatal DA system have yet to be elucidated. The overall objective of this study is to identify the neural pathways (extrapyramidal motor loops) and processes that mediate enhanced striatal glutamatergic activity to produce long-term DA depletions after METH administration. The fact that glutamate can lead to excitotoxicity, oxidative stress, and compromised bioenergetics is well known. Therefore, the critical role of the extrapyramidal circuitry in mediating METH-induced corticostriatal glutamate release and the resultant compromised cellular processes in the striatum as evidenced by free radical damage, impaired cellular energetics, and excitotoxicity also will be assessed. The overarching hypothesis is that METH-induced long-term DA depletions in the striatum are due partly to enhanced extracellular glutamate mediated by increased corticostriatal glutamate overflow. Specifically, increased corticostriatal glutamate release is mediated by multisynaptic mechanisms involving (1) increased striatonigral GABAergic transmission, (2) decreased GABA release in thalamus, and (3) increased glutamate release in cortex. Furthermore, the excitotoxic marker, spectrin proteolysis, and indices of oxidative and metabolic stress will assess the consequences of increased corticostriatal glutamate release following METH. The proposed experiments are unique in that they will begin to address how METH, via the activation of the basal ganglia circuitry, increases corticostriatal glutamate transmission to produce excitotoxicity, impaired cellular energetics, oxidative stress, and ultimately damage to striatal DA terminals. Overall, these experiments have significant clinical implications for the consequences of excitotoxicity in METH abusers and are suggestive of possible parallels between METH-induced neurotoxicity and the pathophysiology of Parkinson's disease.